Methionine aminopeptidases are enzymes that bind to cobalt and manganese ions. The metalloenzymes are widely found in prokaryotic and eukaryotic cells, and exist in three forms, MetAP1A, MetAP1D, and MetAP2. See M. Leszczyniecka et al., Oncogene 25:3471-78 (2006). They are responsible for the removal of the N-terminal methionine residue from nascent proteins, an important step in protein maturation and likely essential for proper functional regulation, intracellular targeting, and protein turnover. See S. M. Arfin et al., Proc. Natl. Acad. Sci. USA 92:7714-18 (1995). Known (irreversible) inhibitors of MetAP2 include the natural product fumagillin and its more potent semi-synthetic analog TNP-470 (AGM-1470). See D. Ingber et al., Nature 348:555-57 (1990); see also E. C. Griffith et al., Chemistry & Biology 4(6):461-471 (1997). Both compounds inhibit angiogenesis, and TNP-470 has been evaluated in numerous clinical trials as a treatment for cancer. See, e.g., R. S. Herbst et al., J. Clin. Oncology 20(22):4440-47 (2002) (non-small cell lung cancer); C. J. Logothetis et al., Clin. Cancer Res. 7:1198-1203 (2001) (progressive androgen-dependent prostate cancer); W. M. Stadler et al., J. Clin. Oncology 17(8):2541-45 (1999) (metastatic renal carcinoma); A. P. Kudelka et al, N. Engl. J. Med. 338:991-92 (1998) (metastatic cervical cancer); A. P. Kudelka et al., Clin. Cancer Res. 3:1501-05 (1997) (squamous cell cancer of the cervix); and P. Bhargava et al., Clin. Cancer Res. 5:1989-95 (1999) (sarcoma, colorectal cancer, and melanoma).
Numerous studies also suggest MetAP2 inhibitors may be used to treat obesity. For example, TNP-470 was tested in various mice obesity models and showed dose-dependent, reversible weight reduction and adipose tissue loss. See M. A. Rupnick et al., Proc. Natl. Acad. Sci. USA 99(16):10730-35 (2002). TNP-470 has also been shown to prevent diet-induced obesity in mice. See E. Brakenhielm, et al., Circulation Research 94(12):1579-88 (2004). Treatment with fumagillin has been shown to impair diet-induced obesity in mice, as evidenced by adipocyte hypotrophy, but without significantly affecting adipose tissue angiogenesis. See H. R. Lijnen et al., Obesity 18(12):2241-46 (2010). Furthermore, a MetAP2 inhibitor, CKD-732, was found to decrease food intake, body weight, fat mass, and the size of adipocytes in genetically and diet-induced obese mice. See Y. M. Kim, et al., J. Mol. Endocrinology, 38:455-65 (2007). Recently, CKD-732 (beloranib hemioxalate) has undergone early-phase clinical testing in adult obese patients (e.g., 30≤BMI≤45 kg/m2).
Some inhibitors of MetAP2 are described in WO 2012/130906 A1, WO 2012/122264 A1, US 2012/004162 A1, WO 2010/065877 A2, WO 2010/065883 A2, WO 2009/117902 A1, WO 2009/073445 A2, WO 2003/027104 A1, WO 2002/042295 A2, US 2002/0151493 A1, U.S. Pat. No. 6,949,584 B2, WO 99/59987 A1, WO 99/59986 A1, WO 98/56372 A1, EP 0359036 A1, and EP 0354787 A1.